2. Academic Validation
  3. Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats

Pharmacokinetics, Tissue Distribution and Excretion of a Novel Diuretic (PU-48) in Rats

  • Pharmaceutics. 2018 Aug 8;10(3):124. doi: 10.3390/pharmaceutics10030124.
Zhi-Yuan Zhang 1,  Hua Zhang 2,  Dan Liu 3,  Ying-Yuan Lu 4,  Xin Wang 5,  Pu Li 6,  Ya-Qing Lou 7,  Bao-Xue Yang 8,  Ya-Xin Lou 9,  Chuang Lu 10,  Qiang Zhang 11,  Guo-Liang Zhang 12
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. [email protected].
  • 2 Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. [email protected].
  • 3 Proteomics Laboratory, Medical and Health Analysis Center, Peking University, Beijing 100191, China. [email protected].
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. [email protected].
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. [email protected].
  • 6 Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. [email protected].
  • 7 Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. [email protected].
  • 8 Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. [email protected].
  • 9 Proteomics Laboratory, Medical and Health Analysis Center, Peking University, Beijing 100191, China. [email protected].
  • 10 Department of Drug Metabolism & Pharmacokinetics (DMPK), Sanofi, Waltham, MA 02451, USA. [email protected].
  • 11 Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. [email protected].
  • 12 Department of Pharmacology, School of Basic Medical Sciences, Peking University, No.38 Xue-Yuan Road, Beijing 100191, China. [email protected].
PMID: 30096833 DOI: 10.3390/pharmaceutics10030124
Abstract

Methyl 3-amino-6-methoxythieno [2,3-b] quinoline-2-carboxylate (PU-48) is a novel diuretic Urea Transporter Inhibitor. The aim of this study is to investigate the profile of plasma pharmacokinetics, tissue distribution, and excretion by oral dosing of PU-48 in rats. Concentrations of PU-48 within biological samples are determined using a validated high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. After oral administration of PU-48 (3, 6, and 12 mg/kg, respectively) in self-nanomicroemulsifying drug delivery system (SNEDDS) formulation, the peak plasma concentrations (Cmax), and the area under the curve (AUC0⁻∞) were increased by the dose-dependent and linear manner, but the marked different of plasma half-life (t1/2) were not observed. This suggests that the pharmacokinetic profile of PU-48 prototype was first-order elimination kinetic characteristics within the oral three doses range in rat plasma. Moreover, the prototype of PU-48 was rapidly and extensively distributed into thirteen tissues, especially higher concentrations were detected in stomach, intestine, liver, kidney, and bladder. The total accumulative excretion of PU-48 in the urine, feces, and bile was less than 2%. This research is the first report on disposition via oral administration of PU-48 in rats, and it provides important information for further development of PU-48 as a diuretic drug candidate.

Keywords

excretion; methyl 3-amino-6-methoxythieno [2,3-b] quinolone-2-carboxylate (PU-48); plasma pharmacokinetics; plasma protein binding; rat; tissue distribution.

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